Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) is a potentially devastating disease associated with mutations in two tumor suppressor genes, TSC1 and 2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin-mediated Rheb activation is PI3K dependent. Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.
Mol Cell 2003 Jun
PMID:Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. 1282 Sep 60

GLP-1, incretin with insulin-independent antidiabetic properties, is insulinomimetic upon glucose metabolism in extrapancreatic tissues, acting through specific receptors not associated to adenylate cyclase activation. We investigated the role of enzymes mediating insulin actions, in the GLP-1-induced glycogen synthase a activation in rat hepatocytes. GLP-1, like insulin, activates PI3K/PKB, p70s6k, p44 and p42 MAP-kinase. Wortmannin (PI3K/PKB inhibitor) blocked the stimulatory action of insulin on glycogen synthase a and reduced that of GLP-1; rapamycin (p70s6k inhibitor) was ineffective and PD98059 (MEK/MAPK inhibitor) decreased only the insulin effect; okadaic acid (PP-2A inhibitor) was ineffective, while TNFalpha (PP-1 inhibitor) blocked the action of insulin and reduced that of GLP-1; H-7 or Ro 31-8220 (PKC inhibitors) decreased the GLP-1 effect, while only H-7 reduced that of insulin. The activation of PI3K/PKB, PKC and PP-1, but not PP-2A, seems to mediate the GLP-1 stimulatory action on glycogen synthase a in rat hepatocytes, while MAPKs and p70s6k could participate in other GLP-1 effects.
Mol Cell Endocrinol 2003 Jun 30
PMID:Cell signalling of the GLP-1 action in rat liver. 1285 Feb 80

IRS-2 plays an important role in the control of pancreatic beta-cell growth, however it is unclear if other IRS family members are also involved. Using recombinant adenoviruses, IRS-1, -2 and -3 expression was varied in the beta-cell line, INS-1. Increased IRS-1 expression had no appreciable effect on beta-cell growth. However, increased IRS-2 expression augmented glucose/IGF-1 induced beta-cell growth mitogenesis and decreased apoptosis due to glucose-deprivation. In contrast, increased IRS-3 expression significantly inhibited mitogenesis and increased apoptosis. IRS-3 was intransiently located to the beta-cell plasma membrane, and appeared to be inert in terms of IGF-1 induced signaling. However, increased IRS-3 expression blocked glucose/IGF-1 induced IRS-2 translocation from the cytosol to the plasma membrane, dampening IRS-2/IGF-1R interaction and subsequent activation of the PI3K/PKB/GSK3 signaling pathway. In contrast, glucose/IGF-1 induced Erk-1/-2 and p70S6K activation were unaffected by IRS-3. These data emphasize the importance of IRS-2/PI3K/PKB signal transduction for beta-cell growth and survival.
Mol Cell Endocrinol 2003 Jun 30
PMID:IRS-3 inhibits IRS-2-mediated signaling in pancreatic beta-cells. 1285 Feb 84

To elucidate the role of mitogen-activated protein kinases (MAPKs) and Akt kinase in leukemogenesis caused by the breakpoint cluster region (BCR)-Abelson (ABL) tyrosine kinase oncoprotein, we examined the activities of MAPKs and Akt kinase and their roles in the action of STI571, a specific inhibitor of BCR-ABL tyrosine kinase, in chronic myelogenous leukemia (CML) cells. We found that extracellular signal-regulated kinase (ERK) 1/2 and Akt kinase are constitutively active in the chronic phase of CML, blast crisis of CML, and the CML-derived K562 cell line. Both interferon-alpha and STI571 suppressed ERK1/2 activity in K562 cells. In contrast, Akt kinase activity was inhibited only by STI571. K562 cell proliferation was markedly suppressed by LY294002, a specific inhibitor of PI3K/Akt kinase, and STI571 but not by PD98059, a specific inhibitor of MEK1/2. In addition, caspase-3 was activated by treatment of cells with STI571 and LY294002 but not with PD98059. These data indicate that Akt kinase may play a role in the proliferation of CML leukemia cells and the action of STI571. Primary leukemia cells from patients with CML blast crisis did not show inhibition of ERK1/2 or Akt kinase activity and were resistant to caspase-3-associated apoptosis after treatment with STI571. These findings suggest that STI571 does not effectively block signaling molecules downstream of the BCR-ABL tyrosine kinase in some cases of CML blast crisis.
Blood Cells Mol Dis
PMID:Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells. 1285 Apr 78

mda-7 is a novel tumor suppressor with cytokine properties. Adenoviral mda-7 (Ad-mda7) induces apoptosis and cell death selectively in tumor cells. The molecular mechanisms underlying the anti-tumor activity of Ad-mda7 in breast and lung cancer lines were investigated. Microarray analyses implicated both the beta-catenin and the PI3K signaling pathways. Ad-mda7 treatment increased protein expression from tumor suppressor genes, including E-cadherin, APC, GSK-3beta, and PTEN, and decreased expression of proto-oncogenes involved in beta-catenin and PI3K signaling. Ad-mda7 caused a redistribution of cellular beta-catenin from the nucleus to the plasma membrane, resulting in reduced TCF/LEF transcriptional activity, and upregulated the E-cadherin-beta-catenin adhesion complex in a tumor cell-specific manner. Expression of the PI3K pathway members (p85 PI3K, FAK, ILK-1, Akt, and PLC-gamma) was downregulated and expression of the PI3K antagonist PTEN was increased. Consistent with this result, pharmacological inhibition of PI3K by wortmannin did not abrogate killing by Ad-mda7. Killing of breast cancer cells by Ad-mda7 required both MAPK and MEK1/2 signaling pathways, whereas these pathways were not essential for MDA-7-mediated killing in lung cancer cells. Thus, in breast and lung tumor cells MDA-7 protein expression modulates cell-cell adhesion and intracellular signaling via coordinate regulation of the beta-catenin and PI3K pathways.
Mol Ther 2003 Aug
PMID:MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells. 1290 43

Androgen-dependent human prostate adenocarcinoma cell line LNCaP was used to study the effect of androgen deprivation on the cell response to TNF-related cytokines. Several signaling pathways were implicated in cell survival in the absence of androgens. In androgen-deprived LNCaP cells, TNF-alpha and TRAIL stimulated the cell growth and activated the mitogenic and antiapoptotic signaling pathways involving NF-kappa B, STAT3, PI3K, and beta-catenin. The results suggested a role of cytokines in the survival of prostate adenocarcinoma cells deprived of androgens in vitro.
Mol Biol (Mosk)
PMID:[Signaling pathways that control the growth and survival of prostate tumor cells in the absence of androgens]. 1294 42

Macrophage migration inhibitory factor (MIF) plays an important role not only in the immune system, but also in tumorigenesis. Lysophosphatidic acid (LPA), a unique lipid mediator, shares several biological functions with MIF, including promotion of tumor cell growth and associated angiogenesis. In this study, we investigated the signaling cross-talk between these two molecules during tumorigenesis and angiogenesis. We first examined the expression of MIF mRNA on a murine colon cancer cell line, colon 26, by LPA. We found that LPA enhanced the expression of MIF mRNA in a dose-dependent manner in vitro. In parallel, LPA stimulated cell growth and up-regulated the vascular endothelial growth factor (VEGF). These effects were dramatically blocked by 21 base double strand (ds) RNA specific for mouse MIF mRNA (RNAi). In vivo, colon 26 cells treated with MIF dsRNA were injected into the backs of mice. The size of tumor volumes became significantly smaller than that of controls. Angiogenesis examined by a Millipore chamber method was also suppressed by the MIF dsRNA. Next, we evaluated the signal transduction pathway relevant to the mitogen-activated protein kinase (MAPK) and Akt/PI3K pathways in response to LPA by RNAi. Ras activation and phosphorylation of Akt and ERK1/2 were strongly suppressed by the dsRNA. On the other hand, tyrosine phosphorylation was minimally changed by the treatment. Taken together, these results suggest that MIF could promote both tumor cell growth and angiogenesis induced by LPA via both the Ras-MAPK and Ras-Akt/PI3K signaling pathways.
Int J Mol Med 2003 Oct
PMID:Induction of macrophage migration inhibitory factor by lysophosphatidic acid: relevance to tumor growth and angiogenesis. 1296 47

Hepatitis B virus x gene product (HBx) is known to be a transactivator of transcriptional elements that regulate the expression of a variety of genes associated with the growth, differentiation, survival and the apoptosis of cells. However, the exact mechanism of the activation and inhibition of cellular events by HBx remains uncertain. The present study was designed to measure the effect of HBx, on the signal transduction pathways associated with intracellular Ca(2+) mobilization following HBx transfection in the stable Chang liver cells (CHL-X). Enhanced cell proliferation by HBx in CHL-X was confirmed by MTT assay and by the immunodetection of PCNA. The transactivation of AP-1 by HBx induced in CHL-X was inhibited by cyclosporin A (CsA), a mitochondrial Ca(2+) channel blocker and by BAPTA-AM, a cytosolic Ca(2+) blocker. Activation of the SAPK/JNK signaling pathway by HBx was evidenced by the increased phosphorylations of c-Jun (Ser63) and of JNK (Thr183/Tyr185). Increased phospho-Erk/Erk and phospho-Raf1/Raf in HBx-induced CHL-X indicated that HBx might stimulate the MAPK pathway. PI3K activity and cytosolic free Ca(2+) levels were elevated in HBx-induced CHL-X. These results imply that HBx transactivates both JNK and MAPK signal transduction pathways in association with the mobilization of cytosolic Ca(2+).
Exp Mol Med 2003 Aug 31
PMID:Activation of calcium signaling by hepatitis B virus-X protein in liver cells. 1450 71

Basic fibroblast growth factor (bFGF) belongs to the large set of intratesticular regulators that provide the fine tuning of cellular processes implicated in the maintenance of spermatogenesis. The aim of the present study was to determine the participation of mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase/protein kinase B (PI3K/PKB) pathways in bFGF regulation of Sertoli cell function. Twenty-day-old rat Sertoli cell cultures were used. Stimulation of the cultures with bFGF showed a time-dependent increment in phosphorylated MAPK and PKB levels that reached maximal values in 5-min incubations. MAPK kinase inhibitors U0126 (U) and PD98059 (PD) and a PI3K inhibitor wortmannin (W) were able to block the stimulatory effects of bFGF on phosphorylated MAPK and PKB levels respectively. The participation of MAPK- and PI3K/PKB-signaling pathways in the regulation by bFGF of two well-known Sertoli cell-differentiated functions, lactate and transferrin production, was next explored. As for lactate production, PD and W did not modify the ability of bFGF to stimulate lactate production. However, a combination of PD and W partially impaired the increase in lactate production elicited by bFGF. The participation of MAPK- and PI3K/PKB-signaling pathways in the regulation by bFGF of glucose uptake and lactate dehydrogenase (LDH) activity was also analysed. In this respect, it was observed that W markedly decreased basal and bFGF-stimulated glucose uptake and that U and PD did not modify it. On the other hand, U and PD decreased the stimulation of LDH activity by bFGF whereas W did not modify it. As for transferrin production, while both MAPK kinase inhibitors partially decreased the ability of bFGF to stimulate transferrin secretion, the PI3K inhibitor did not modify it. In summary, the results demonstrated that bFGF stimulates MAPK- and PI3K/PKB-dependent pathways in rat Sertoli cells. Moreover, these results showed that while bFGF utilizes the MAPK pathway to regulate transferrin production and LDH activity, it uses the PI3K/PKB pathway to regulate glucose transport into the cell.
J Mol Endocrinol 2003 Oct
PMID:Assessment of the roles of mitogen-activated protein kinase and phosphatidyl inositol 3-kinase/protein kinase B pathways in the basic fibroblast growth factor regulation of Sertoli cell function. 1451 96

Lysophosphatidic acid acyltransferase beta (LPAAT-beta) is an intrinsic membrane protein that catalyzes the synthesis of phosphatidic acid (PA) from lysoPA. Given that PA is a cofactor in a number of signaling cascades that are constitutively active in tumors, we evaluated the role of PA produced by LPAAT-beta in Xenopus oocyte meiotic maturation assays and an isoform-specific inhibitor of LPAAT-beta in mammalian cell assays. We found that ectopic overexpression of LPAAT-beta cooperates in activation of the Ras/Raf/Erk pathway in Xenopus oocytes and that inhibition of LPAAT-beta inhibits signaling in both the Ras/Raf/Erk and PI3K/Akt pathways. When LPAAT-beta activity is suppressed by CT32228 (N-(4-bromo-phenyl)-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine-2,4-diamine), an isoform-specific noncompetitive inhibitor, tumor cells undergo mitotic catastrophe while most normal cells simply arrest or become quiescent. The data presented here suggest that PA produced by LPAAT-beta plays an important role in signaling pathways critical to tumor cell survival.
Mol Cancer Ther 2003 Oct
PMID:Inhibition of lysophosphatidic acid acyltransferase beta disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells. 1457 72


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>